Amlodipine and vascular hypertrophy.

In both atherosclerosis and arterial hypertension, structural and functional abnormalities result in vascular hypertrophy that is associated with an increased ratio of vascular media thickness to lumen diameter and hyperreactivity of vascular smooth muscle cells (VSMCs), resulting in uncontrolled cell migration and growth in vivo. In culture, VSMCs isolated from the spontaneously hypertensive rat (SHR) also display exaggerated growth and/or proliferation compared to VSMCs isolated from normotensive control Wistar Kyoto (WKY) rats. In vitro studies of cultured VSMCs can therefore be used as a model to investigate the mechanisms whereby a drug such as amlodipine can exert its antihypertensive and antiatherogenic effects. The present in vitro investigations examine the mechanisms whereby amlodipine reduces VSMC growth/proliferation promoted by basic fibroblast growth factor (bFGF), a peptide growth factor likely to participate in the vascular smooth muscle hypertrophy of the SHR. VSMCs from SHR and/or WKY rat aortae were isolated, passaged, and cultured. The influence of amlodipine on VSMC growth/proliferation was studied by measuring DNA synthesis and cell number under experimental conditions, which allowed us to determine the cell cycle phase in which amlodipine exerts its effects. Amlodipine was found to inhibit growth and bFGF-induced DNA synthesis in a concentration-dependent manner. Delayed addition of amlodipine showed that the drug exerts its effect early in the G1 phase, a result that was confirmed by the finding that amlodipine could not inhibit bFGF-induced DNA synthesis in VSMCs arrested at the G1/S boundary. In comparative experiments, the inhibitory effect of amlodipine on both cell growth and DNA synthesis was found to be of similar magnitude in SHR- and WKY-derived VSMCs. It is therefore likely that by modulating cell growth/proliferation induced by bFGF, amlodipine may reduce the vascular hypertrophy of the SHR. Since amlodipine also has been found to inhibit VSMC migration, one may reasonably envisage that these characteristics are important components of the antiatherogenic properties of the drug.